The present invention relates to a phenobarbital sodium solution formulation that is more stable under various stress conditions then prior art formulations and that includes a reduced impurity profile and faster dissolution rate.
A number of phenobarbital injection USP products are currently available on the US and international markets for various treatments, including as a medication for partial and generalized tonic-clonic seizures as well as for treatment of neonatal seizures. The injectable form is primarily used to control status epilepticus.
To prepare phenobarbital sodium formulations for injection, the compound is typically dissolved in a solvent. While the compound is freely soluble in water with solubility reported to be as high as 333 mg/mL to 1 g/mL), the presence of hydroxyl ions in the formulation from the water results in a hydrolysis pathway that can destroy the phenobarbital ring complex. This destruction results in the possible formation of impurities including harmful degradants or precipitates. Furthermore, some of the impurities do not possess a chromophore and therefore are not capable of detection by standard UV-Vis detectors with HPLC analytical methodology. Thus, it is desired to minimize or preferably eliminate any impurities in commercial phenobarbital sodium injection formulations.
The solution to the problem then easily becomes removal of water from the formulation. This is easier said than done as it is highly difficult to dissolve phenobarbital sodium in any organic solvent alone, even when utilizing an aggressive turbulent flow for mixing the active and solvent together. Instead, the prior art generally suggests that a common method for minimizing phenobarbital degradation in solution dosage forms is to dissolve the drug in a mixed solvent of water with organic solvents such as alcohol, sorbitol, propylene glycol, glycerol, polyethylene glycol, and others. This assumes and requires the inclusion of some water for dissolution purposes. As phenobarbital sodium is not as soluble in solvents such as, e.g., ethanol, with solubility reported to only be as high as 100 mg/mL, some water is typically included in formulations that include ethanol or other liquids as primary solvents. The water content, in general, is on the order of 8 to 12% by weight or more of such solvent mixtures.
The typical impurities for phenobarbital solutions that include water as part of the solvent system are phenyl ethyl acetyl urea (PEAU) and phenyl butyric acid (PBA). Currently, the limits for such impurities in commercially marketed pharmaceutical products are up to 10% of PEAU and up to 1.0% of PBA. The impurities are measured after storage of the solution at room temperature for 2 years. As an accelerated test, the impurities are measured after storage of the solution at a temperature of 40° C. for three months. Room temperature is defined as “near 25° C.” and is typically understood as being between the ordinary temperatures of approximately 18.3° C. to 26.7° C. of the atmosphere in a laboratory.
Other possible degradation products of phenobarbital sodium can result from other conditions, such as reactions with base, oxidation or subjecting the compound to heat. These degradation products are illustrated in Table 1 below:
TABLE 1Degradation Products of Phenobarbital Sodium
The following prior art documents are cited as particular examples of solvent mixtures that have been used for phenobarbital sodium solutions or for other pharmaceuticals that cannot be solubilized in water.
U.S. Pat. No. 6,627,211, which discloses a solvent mixture for transmucosal delivery of an anticonvulsant agent, such as a diazepam, wherein the solvent mixture comprises, e.g., 30% of a C1-C5 aliphatic alcohol such as ethanol, 60% of a glycol such as propylene glycol and 10% water along with a biological surfactant of a bile salt or lecithin to assist in the transmucosal permeation of the anticonvulsant agent.
U.S. Pat. No. 5,141,961, which discloses a process for solubilizing various pharmaceuticals that are difficult to solubilize in water. These pharmaceuticals are solubilized in a mixture of a polyethylene glycol and a polyvinylpyrrolidone. A typical formulation includes 20% to 70% of propylene glycol along with 1 to 28% of a polyvinylpyrrolidone and a water content that is 8% or less. A solvent of a C1-C4 aliphatic alcohol, typically ethanol, can be used in an amount of 1 to 50% to prepare mixtures of the ingredients but thereafter is evaporated from the formulation.
US patent publication 2006/0153905 discloses transdermal or transmucosal pharmaceutical formulations that include at least one pharmacologically active ingredient, and a solvent system having a monoalkylether of diethylene glycol and a glycol present in specified ratios, and a mixture of water and alcohol. The document discloses the use of 6% propylene glycol and 47% ethanol with water and other components.
PCT publication WO 2006/125774 discloses an oral formulation of topiramate that has a low water content to prevent hydrolysis of the active and to extend the storage life of the formulation. The water content of such formulations is no more than 5%. The solvents that are used include ethanol, propylene glycol, or polyethylene glycols, alone or in various combinations. These solutions also contain various preservatives and antioxidants in order to form stable solutions at pH values of 5 to 8.
An article by Gupta, V. D., Effect of ethanol, glycerol and propylene glycol on the stability of Phenobarbital Sodium, J. Pharm. Sci., 1984, 73:1661-2, reports on the effects that these solvents have on the stability of phenobarbital solutions. For stabilization, Gupta discloses that ethanol had the best effect followed by propylene glycol and glycerol compared to the stability of phenobarbital in water alone. The preferred solutions included 20% of ethanol, propylene glycol or glycerol in water. As noted herein, however, such a large amount of water is not desirable from the standpoint that it will likely cause hydrolysis of the phenobarbital ring and the generation of undesirable impurities.
A number of other prior art documents disclose the stability of phenobarbital in various aqueous solutions that can contain propylene glycol, ethanol, or other solvents. As noted, however, such aqueous solutions are not desirable in pharmaceutical products due to the generation of impurities over time.
An article by Williams, N. A. et al., “Excess free energy approach to the estimation of solubility in mixed solvent systems III: Ethanol-propylene glycol-water mixtures,” J. Pharm Sci (January, 1984), 73(1): 18-23, describes the applicability of the Wohl excess free energy expression to describe the solubility of phenobarbital in various mixtures including ethanol or propylene glycol combined together or with water. Williams concludes that the equation does not satisfactorily describe solubility for phenobarbital in ethanol/propylene glycol solutions even though solubility is fairly high because the assumptions made in the derivation of the equation do not hold, but that the equation is acceptable for describing the solubility of solutions that contain water.
As noted, the inclusion of significant amounts of water in phenobarbital sodium formulations is not desirable as it will likely result in the formation of undesirable amounts of impurities. Thus, there is a need for formulations that contain or generate relatively low amounts of such impurities. The present invention now addresses the need for stable, essentially impurity-free formulations.